Drug eluting stents (DES) have decreased

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1 JACC: CARDIOVASCULAR IMAGING VOL. 5, NO. 11, 1 1 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN X/$36. PUBLISHED BY ELSEVIER INC. BRIEF REPORT OCT-Verified Peri-Strut Low-Intensity Areas and the Extent of Neointimal Formation After 3 Years Following Stent Implantation Jin-Ho Choi, MD, PHD,* Juan F. Granada, MD, Jung-Sun Kim, MD, PHD, Young Bin Song, MD, PHD,* Joo-Yong Hahn, MD, PHD,* Seung Hyuk Choi, MD, PHD,* Armando Tellez, MD, Krzysztof Milewski, MD, Myeong-Ki Hong, MD, PHD, Yangsoo Jang, MD, PHD, Sang Hoon Lee, MD, PHD,* Hyeon-Cheol Gwon, MD, PHD* Seoul, Korea; and New York, New York Drug eluting stents (DES) have decreased substantially the neointimal formation after percutaneous coronary intervention (PCI). However, DES are not free from neointimal hyperplasia (NIH) and stent thrombosis, which are related to the delayed arterial healing following DES implantation. The recently introduced optical coherence tomography (OCT) enables a detailed investigation of vessel healing. The presence of peri-strut low intensity (PLI) has been described as a potential marker of abnormal neointimal healing (1,). We investigated the late healing characteristics of stents implanted over 3 years, specifically the potential impact of PLI on NIH and restenosis. OCT imaging (M, Lightlab Imaging, Westford, Massachusetts) was performed in 99 patients who were treated with bare-metal stents (BMS), sirolimus-eluting stents (SES) (Cypher, Cordis, Bridgewater, New Jersey), or paclitaxeleluting stents (PES) (Taxus, Boston Scientific, Natick, Massachusetts) from September 7 to From the *Department of Medicine, Samsung Medical Center, Cardiac and Vascular Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Emergency Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Skirball Center for Cardiovascular Research, Cardiovascular Research Foundation, Columbia University Medical Center, New York, New York; and the Division of Cardiology, Severance Cardiovascular Center, Yonsei University College of Medicine, Seoul, Korea. Support was provided by Clinical Research Development (CRS18-8-1) of Samsung Medical Center. All authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received January 6, 1; revised manuscript received February 8, 1, accepted February 9, 1. August 9. The inclusion criteria were stent implanted in de novo lesion and time from index PCI 3 years. The exclusion criteria were left main, stent thrombosis, or target lesion revascularization. Cross-sectional images of the stented segments were analyzed at 1-mm intervals. PLI was defined as homogenous low-intensity area around a stent strut without significant signal attenuation behind the area on a strut basis. The severity of PLI on a cross-sectional basis was evaluated semiquantitatively by PLI score by the extent of PLI occupying the number of quadrants. Neointimal thickness and malapposition of each strut, neointimal lipid pool, calcification, microvessel, and OCT-derived thin cap neoatheroma (OCT- TCNA) were also defined (Fig. 1A) (3). A total of 3,365 OCT cross sections from 15 stents were assessed. After exclusion of overlapping stents (,197 struts [6.7%]) and side branches mm (77 struts [.8%]), a total of 3,3 struts (9%) and 3,53 cross sections were included in the analysis. By the OCT strut-level analysis, PLI was most common in BMS (19.%), followed by PES (1.6%) and SES (6.%; p.1) (Table 1). NIH was higher in struts displaying PLI than struts without PLI in all stents (p.1 for all). Interestingly, the NIH thickness was.3 mm even in the BMS strut without PLI, and it was.5 mm in SES struts with PLI (Fig. 1B). Significant correlation between the severity of PLI and the degree of NIH was found in both the cross-sectional and stent-level analyses (r.537 to.86; p.5) (Fig. 1B, Table 1). The frequency of OCT-TCNA per stent was 7.9% to

2 JACC: CARDIOVASCULAR IMAGING, VOL. 5, NO. 11, 1 NOVEMBER 1: Figure 1. Representative Images of PLI and Impact of PLI on Strut-Level Neointimal Thickness and Stent-Level Angiographic Late Loss (A) Representative optical coherence tomography (OCT) findings of neointima. Peri-strut low intensity (PLI) (white arrows) is seen as homogenous lower intensity adjacent to stent struts. PLI score is defined as the number of quadrants, to, occupied by PLI. PLI may appear granular as shown by image in the rightmost middle row. OCT-derived thin cap neoatheroma (OCT-TCNA) was defined as the presence of TCNA having an angle of signal-poor lipid pool (blue arrowhead) in quadrants and a fibrous cap thickness 65 m (pink arrows) in 3 consecutive images. Microvessels are small vesicular tubular structures (pink arrows) visible in 1 cross-sectional image. Neointimal calcification is a well-delineated signal-poor mass with a sharp border (blue arrowhead). Continued on the next page. 15.6% and not different between stent types (p nonsignificant) (Table 1). The severity of PLI correlated with angiographic late loss in all groups (r.7 to.583; p.5) (Fig. 1B, Table 1). The presence of PLI in one quadrant of OCT image was related to a 6.6- to 13.-fold increase of binary restenosis after adjustment for stent area (p.5) (Table 1). The vascular healing response of BMS implantation is known to be initial regression of neointima followed by a plateau at least up to 3 years, whereas that of DES is a mild but continuous growth. Little is known about the characteristics of late neointima. Our study showed that PLI is a common finding long after stent implantation and appears to be involved in neointimal proliferation.

3 1158 JACC: CARDIOVASCULAR IMAGING, VOL. 5, NO. 11, 1 NOVEMBER 1: B1 Distribution of Neointimal Thickness Over Strut 7 1,.19±.18 mm 3,.1±.15 mm 6.9±.18 mm 8, p<.1.6±.3 mm 6 p<.1.7±.7 mm, 1,5 1, 5 p<.1.56±.31 mm Neointimal Thickness (mm) Neointimal Thickness (mm) Neointimal Thickness (mm) PLI (-) PLI (+) B Mean Neointimal Area (mm ) B3 5 r =.736, p<.1 r =.611, p< r =.83, p< Late Loss (mm) r =.583, p = r =.7, p = r =.6, p = Figure 1. Continued (B1) Distribution of neointimal thickness by PLI in strut level. The neointimal thickness over struts with PLI (light blue bars) was higher than neointimal thickness over struts without PLI (red bars) in all stent types (all p.1). Even the neointimal thickness of sirolimus-eluting stents (SES) with PLI was higher than those of bare-metal stents (BMS) without PLI ( mm vs mm; p.1). Correlation between severity of PLI and degree of neointimal hyperplasia or angiographic late loss is shown in B and B3, respectively. PES paclitaxel-eluting stents. The histopathology of PLI is still not known well. PLI was correlated with the quality of the neointima with different stent types (,,5). In our study, the presence of PLI was the strongest factor related to neointimal proliferation. Considering contribution of continuous inflammation, fibrin deposition, extracellular matrix accumulation, or formation of neoatherosclerosis to

4 JACC: CARDIOVASCULAR IMAGING, VOL. 5, NO. 11, 1 NOVEMBER 1: Table 1. Strut-Level, Cross-Sectional, and Stent-Level OCT Analysis p Value Strut-level analysis N 7,7 7,551 15,11 Neointimal thickness, mm Uncovered strut 1. (9) 9.1 (686) 11. (1,6).1 Malapposed strut (3) 1.7 (13). (35).1 Strut with PLI 19. (1,51) 1.6 (955) 6. (97).1 Cross-sectional level analysis N Stent area, mm Luminal area, mm Neointimal area, mm Neointimal area, % No. of PLI PLI score Lipid pool 8.5 (63).1 (3) 3. (7).1 Microvessel 15.9 (118). (17) 1.9 (3).1 Calcification. (3).7 (5).3 ().1 Correlation between neointimal area and r.6 r.5 r.593.1* no. of PLI Stent-level analysis N Left anterior descending artery lesion 59. (19) 6. (18) 66.7 ().37 Imaged length, mm Imaged length, %* Stent length, mm Volumetric obstruction, % Volumetric obstruction, mm Any PLI within stent 87.5 (8) 8. () 66.7 ().7 Mean PLI score Lipid pool 59.3 (19) 33.3 (1) 15.9 (1).1 OCT-TCNA 15.6 (5) 13.3 () 7.9 (5).9 Correlation between mean neointimal r.736 r.611 r.83.1* area and strut with PLI Angiographic binary restenosis and OCT imaging Mean PLI score per stent 6.61 (7 7.8) 5.93 ( ) 19.9 ( ) Stent area, mm.9 (.559 1).6 (.11 1.).988 (.68 55) Values are mean SD, n (%), or odds ratio (95% confidence interval). The Kruskal-Wallis test was used for comparison among stent types. p Value among 3 stent types, except *Pearson s correlation coefficient (p.5) and odds ratio of multivariate logistic regression analysis (p.5). BMS bare-metal stent(s); OCT optical coherence tomography; OCT-TCNA OCT-derived thin cap neoatheroma; PES paclitaxel-eluting stent(s); PLI peri-strut low intensity; SES sirolimus-eluting stent(s). the late neointimal growth, PLI may be the trace of burnt-out neointimal growth or sustained residual biological process occurring adjacent to the stent. The limitations of this study are its crosssectional nature and lack of neointimal histology. The histological validation and serial examination of our findings deserve further investigation because they may have clinical implications among patients undergoing stent implantation. Reprint requests and correspondence: Dr. Hyeon-Cheol Gwon, Department of Medicine, Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 5 Irwon-dong, Gangnam-gu, Seoul , Korea. hcgwon6@gmail.com.

5 116 JACC: CARDIOVASCULAR IMAGING, VOL. 5, NO. 11, 1 NOVEMBER 1: REFERENCES 1. Teramoto T, Ikeno F, Otake H, et al. Intriguing peri-strut low-intensity area detected by optical coherence tomography after coronary stent deployment. Circ J 1;7: Inoue T, Shite J, Yoon J, et al. Optical coherence evaluation of everolimuseluting stents 8 months after implantation. Heart 11;97: Kim JS, Jang IK, Fan C, et al. Evaluation in 3 months duration of neointimal coverage after zotarolimus-eluting stent implantation by optical coherence tomography: the ENDEAVOR OCT trial. J Am Coll Cardiol Intv 9;: Miyoshi N, Shite J, Shinke T, et al. Comparison by optical coherence tomography of paclitaxel-eluting stents with sirolimus-eluting stents implanted in one coronary artery in one procedure 6- month follow-up. Circ J 1;7: Tanaka N, Terashima M, Rathore S, et al. Different patterns of vascular response between patients with or without diabetes mellitus after drugeluting stent implantation: optical coherence tomographic analysis. J Am Coll Cardiol Intv 1;3:17 9. Key Words: optical coherence tomography y peri-strut low intensity y stent